Project 2: The New Era of Cellular Therapies For Lung Transplant Tolerance

项目 2：肺移植耐受细胞疗法的新时代

• 批准号: 10622128
• 负责人: Leslie S Kean
• 金额: $ 106.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-23 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622128
• 关键词: Ablation; Address; Allograft Tolerance; Antibodies; Antibody-drug conjugates; Antigens; Area; Autoimmune Diseases; Biotechnology; Bone Marrow; Calcineurin inhibitor; Cell Therapy; Characteristics; Chimerism; Chronic; Clinical; Data; Defect; Development; Drug Kinetics; Engineering; Environment; Equilibrium; FOXP3 gene; Goals; Half-Life; Human; Immune; Immune Targeting; Immune Tolerance; Immunity; Immunomodulators; Immunosuppression; Infection; Inflammatory; Infusion procedures; Kidney; Knock-out; Life; Lung; Lung Transplantation; Lymphoproliferative Disorders; Maintenance; Marrow; Monoclonal Antibodies; Mus; PTPRC gene; Patient-Focused Outcomes; Protocols documentation; Public Health; Regimen; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; Risk; Safety; Signal Transduction; Sirolimus; Specificity; Steroid Resistance; Steroids; T-Cell Activation; T-Lymphocyte; TNFSF4 gene; TNFSF5 gene; Testing; Toxic effect; Transplantation; Transplantation Tolerance; Treg therapy; Virus; allograft rejection; base editing; chemotherapy; chimeric antigen receptor; clinical translation; conditioning; design; evidence base; graft vs host disease; high risk; immunoregulation; improved; innovation; insight; irradiation; isoimmunity; lung allograft; lung basal segment; nonhuman primate; novel; novel strategies; post-transplant; preservation; success; synergism

PROJECT SUMMARY / ABSTRACT The current half-life of a lung allograft is unacceptably short at just 6.7 years, and all recipients encounter significant complications, both from allograft rejection and from immunosuppression-associated toxicities. Immune tolerance provides the ultimate solution to these issues, with the promise of life-long graft acceptance without chronic immunosuppression, and, or critical importance, with maintenance of protective immunity. While tolerance to kidneys has been achieved in non-human primates (NHPs) and humans with transient mixed chimerism, the same protocols have thus far failed for lungs. Importantly, however, we have recently successfully induced durable (ie stable for the life of the transplant) mixed-chimerism and tolerance during NHP lung transplantation, representing a major advance. However, this first success employed non-clinically available agents and conferred a high risk of post- transplant lymphoproliferative disorder (PTLD). These data suggest that durable chimerism-based lung transplant tolerance is possible, but that improved strategies are needed, to reset recipient immunity towards tolerance, preserve protective immunity, and enable rapid clinical translation. To address these goals, Project 2 focuses on 3 areas: 1) Developing safe, targeted bone marrow conditioning regimens for chimerism-induction; (2) Discovering Treg-supportive immunomodulation strategies; and (3) Engineering optimal CD4+/FoxP3+ regulatory T cell (Treg)- based cellular therapies, to enhance and stabilize chimerism-based immune tolerance. We do so through the following two Specific Aims: Aim 1: CD45-antibody-drug-conjugate (ADC)-based conditioning and targeted immunomodulation: the new era of mixed-chimerism induction for clinical translation. Aim 1 encompasses 3 Objectives: (1) To test the hypothesis that a CD45-ADC can successfully create marrow and immune space. (2) To test the hypothesis that Treg- supportive, tolerogenic immunomodulation, through anti-OX40L, CD137-ADC, or anti- CD154, will successfully induce durable chimerism across MHC barriers and maintain protective immunity. (3) To test the hypothesis that CD45-ADC- based chimerism and targeted immune modulation can induce lung allograft tolerance by establishing a Treg- supportive systemic and intragraft environment. Aim 2: Engineering an optimal Treg cellular therapy to augment chimerism-based tolerance induction. Aim 2 encompasses 3 Objectives designed to optimize Treg safety/efficacy for chimerism- and tolerance-induction. (1) To test the hypothesis that OX40L- or CD83-CAR-Tregs will be more suppressive than unmodified Treg, and will enhance control of inflammatory signaling, inhibit alloreactivity, and stabilize chimerism. (2) To test the hypothesis that Tregs that are base-edited to enforce FOXP3 expression and be resistant to calcineurin inhibitors, sirolimus, and/or steroids, will be maximally persistent and stable after infusion. (3) To test the hypothesis that these Tregs will optimize chimerism- based lung allograft tolerance, by reinforcing a Treg- supportive systemic and intragraft environment. Together, these Aims are designed to develop innovative approaches for durable chimerism-based lung transplant tolerance.

项目摘要 /摘要 肺同种异体移植物的当前半衰期仅在6。7年的时间内就无法接受，并且所有接受者都遇到了重要的 来自同种异体移植排斥和免疫抑制相关毒性的并发症。免疫耐受性 在没有慢性的情况下，提供了终身嫁接的承诺，为这些问题提供了最终解决方案 免疫抑制和或至关重要，并维持保护性免疫。而对肾脏的容忍度 在非人类灵长类动物（NHP）和具有短暂混合嵌合的人类中实现了相同的方案 到目前为止，肺部未能通过。但是，重要的是，我们最近成功地引起了耐用（即 NHP肺移植期间的混合神经和耐受性，代表了重大进展。 但是，第一个成功采用了非临床可用的代理，并赋予了移植后的高风险 淋巴增生性疾病（PTLD）。这些数据表明，耐用的基于嵌合主义的肺移植耐受性是 可能需要改进的策略，以重置接受者对宽容的免疫力，保持保护性 免疫力，并实现快速的临床翻译。为了解决这些目标，项目2侧重于3个领域：1）开发 安全的，有针对性的骨髓调节方案，用于嵌合诱导； （2）发现特雷格支持 免疫调节策略； （3）工程最佳CD4+/FOXP3+调节T细胞（Treg）基于细胞 疗法，以增强和稳定基于嵌合的免疫耐受性。我们通过以下两个特定的 目的：目标1：基于条件和靶向免疫调节的CD45-抗体 - 毒物偶联（ADC）： 临床翻译的混合学诱导的新时代。目标1包括3个目标：（1）测试 CD45-ADC可以成功创建骨髓和免疫空间的假设。 （2）检验以下假设 通过抗OX40L，CD137-ADC或抗CD154的支持性，耐受性免疫调节将成功诱导 跨MHC屏障并保持保护性免疫力的持久性嵌合。 （3）检验CD45-ADC-的假设 基于嵌合的嵌合和靶向免疫调节可以通过建立Treg- 支持性的系统和内部环境。 AIM 2：设计最佳的Treg蜂窝疗法以增加 基于嵌合的耐受性诱导。 AIM 2包含3个旨在优化Treg安全/功效的目标 用于嵌合和耐受性诱导。 （1）检验OX40L-或CD83-CAR-Tr​​egs将更多的假设 抑制性比未修饰的Treg，将增强对炎症信号的控制，抑制同种异体反应性和 稳定嵌合。 （2）检验以下假设：基础编辑以强制foxp3表达和be 在输注后，对钙调神经磷酸酶抑制剂，西罗莫司和/或类固醇具有抗性。 （3） 为了检验这些Tregs将通过增强Treg-的假设来优化基于Chimerism的肺同种异体移植能力 支持性的系统和内部环境。这些目标共同旨在开发创新的方法 用于持久基于嵌合的肺移植耐受性。